1-propargyloxy-2-carbamoyloxy-3-propyloxy propane



United States Patent 3,527,788 1-PROPARGYLOXY-Z-CARBAMOYLOXY- 3-PROPYLOXY PROPANE Michel Louis Delalande, Paris, France, assignor to Delalande S.A., Courbevoie, Hauts-de-Seine, France, a corporation of France No Drawing. Filed July 26, 1966, Ser. No. 567,861 Claims priority, application Great Britain, July 27, 1965, 31,936/ 65 Int. Cl. C07c 101/00 US. Cl. 260-482 1 Claim ABSTRACT OF THE DISCLOSURE A compound of the formula CHz-O-CHz-CECH H2ORa in which R is hydroxyl or -O-CO--NH R is selected from the group consisting of 1) a lower aliphatic hydrocarbyl;

(2) a cycloalkyl radical;

(3) an w-chloroalkyl radical in which the alkyl contains from 2 to 4 carbon aotms;

(4) a morpholinoalkyl radical in which the alkyl contains from 2 to 4 carbon atoms;

(5) a benzene nucleus and a benzene nucleus substituted with one or more members selected from the group consisting of (a) an alkyl containing from 1 to 3 carbon atoms,

(b) an acyl containing 2 or 3 carbon atoms,

(c) chloro,

(d) trifluoromethyl;

(6) an arylaliphatic radical;

(7) an aryloxyalkyl radical;

(8) an a or B naphthyl radical.

This invention relates to derivatives of propargylic ethers of propane.

According to one aspect of the present invention there is provided derivatives of propargylic ethers of propane having the general formula R is hydroxyl or O--CONH R is selected from the group consisting of (1) a lower aliphatic hydrocarbyl including saturated hydrocarbyls, such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl and pentyl, and unsaturated hydroc-arbyls such as allyl and p p y (2) a cycloalkyl radical, such as cyclopentyl and cyclohexyl;

(3) an w-chloroalkyl radical containing 2 to 4 carbon atoms;

(4) a morpholinoalkyl radical in which the alkyl contains 2 to 4 carbon atoms;

(5 a benzene nucleus which may be substituted with one or more members selected from the group consisting of (a) an alkyl containing 1 to 3 carbon atoms, (b) an acyl containing 2 or 3 carbon atoms, (0) chloro,

3,527,788 Patented Sept. 8 1970 (d) trifluoromethyl; (6) an arylaliphatic radical, such as benzyl, cinnamyl, phenylisopropyl and phenethyl; (7) an aryloxyalkyl radical, such as phenoxyethyl; (8) an a or e naphthyl radical.

R may be a methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl or amyl radical or it may be an allyl or propargyl radical. Again R may be a 2-chloroethyl, 3- chloroethyl, 3-chloropropyl or a 4-chlorobutyl radical.

According to another aspect of the present invention the aforesaid derivative in the case when R is OH may be prepared by a process which comprises reacting on epoxypropane of formula CH2 i a dlH2O-(CHz)-CECH with a compound of formula R OM where R has the same meaning as above and M is hydrogen or an alkali metal.

In such a process, the epoxy-propane is 1-propargyl-2,3- epoxy propane. -In this case the reaction may be carried out in an anhydrous medium in the presence of boron trifluoride etherate.

According to a third aspect of the present invention the aforesaid derivative in the case when R is OH may be prepared by a process in which a l-alkoxy or -1-aryloxy- 2,3-epoxypropane of formula JHzO-R7 where R, is an alkyl or aryl group is reacted with an alcohol of formula where q is 0 or an integer from 1 to 3 inclusive.

In this process q is preferably 0, the alcohol being propargyl alcohol. In the last embodiment the reaction is carried out in an anhydrous medium in the presence of boron trifluoride etherate.

According to yet another aspect of the present invention the aforesaid derivative in the case When R is OH may be prepared by a process in which a compound of formula where R; is an alkyl or aryl group is first halogenated and then dehydrohalogenated.

In a preferred embodiment of the said process the derivative may be first brominated and then dehydrobrominated. Bromination may be carried out by treating the compound with bromine in carbon tetra-chloride and dehydrobromination by treating the product of bromination with sodarnide in liquid ammonia.

The process which may be used when the radical to be introduced is a phenol radical, consists substantially in heating 1-propargyloxy-2,3 epoxypropane with alkaline phenolate for approximately 2 hours. The desired product is extracted by means of ether from the reaction mixture which has previously been cooled. The ether is then removed from the volatile solution obtained, the desired product being distilled under reduced pressure in a neutral atmosphere.

The following examples illustrate the preparation of certain compounds according to the invention.

3 EXAMPLE 1 l-Propargyloxy-3-n-propyloxy-2-propanol One mol of l-propargyloxy-Z,3-epoxypropane is introduced drop by drop and at a temperature between 60 and 70 into a mixture of 3 mols of n-propanol and 8 ml. of a solution of 3% boron trifiuoride in ether with vigorous stirring.

During the whole of this addition, the temperature is kept at 70 C. and then left in contact for -20 minutes.

The mixture is cooled and ml. of water added again with vigorous agitation.

The excess propanol is removed at 4045 C. under 50 mm. Hg. The product is then distilled under reduced pressure and in a nitrogen atmosphere E/O.3:84.

EXAMPLE 2 l-Propargyloxy-3-benzyloxy-2-propanol 1 mol of l-propargyloxy-2,3-epoxypropane-2,3 is introduced drop by'drop, with agitation, into a mixture of 3 mols of benzyl alcohol and 8 ml. of a 0.3% solution of boron trifiuoride, the mixture being previously heated to 50 C.

The reaction is exothermal so that the preparation must be cooled externally to keep the internal temperature at 60 C. The mixture is then left in contact at ordinary temperature for 1 hour.

20 ml. water are added whilst agitating the mixture. A separation is then effected by distillation of benzyl alcohol (E/1.4:77). Then the desired product is distilled under reduced pressure and in a nitrogen atmosphere: E/0.001:140 C.

EXAMPLE 3 l-Propargyloxy-3 -phenoxy-2-propanol A mixture of 1-propargyloxy-2,3-epoxypropane (0.75 mol) and of sodium phenolate (1.3 mol of phenol+0.9 mol NaOH+300 ml. water), is heated for two hours at 60 C. with agitation.

The mixture is allowed to cool and extracted twice with 200 ml. ether each time. The volatile solution is first washed with a sodium solution, then twice in water. Drying is effected over sodium sulphate; the ether is removed and the product distilled under reduced pressure in an atmosphere of nitrogen: E/0.005:125 C.

EXAMPLE 4 I-Propargyloxy-3-n-propyloxy-2-carbamyl propane The mixture is washed twice with 200 ml. water. The toluene is then removed and the product distilled under reduced pressure in a nitrogen atmosphere: E/0.04:

EXAMPLE 5 l-Propargyloxy-3-benzyloxy-2-carbamyl propane 1 mol of l-propargyloxy-3-benzyloxy-2 propanol is treated in the presence of 1 mol of diethyl aniline with 1.5 mol of phosgene in toluene solution.

The resultant hydrochloride is separated by addition of water and the excess phosgene is removed. The chlorocarbonate of the diether alcohol formed is then treated without isolating it from the reaction mixture in a stream of gaseous ammonia.

The mixture is washed twice with 200 ml. water. Half the toluene is removed and the product allowed to crystallise. After drying and washing in petroleum ether a product of M.P. 62 C. is obtained.

EXAMPLE 6 l-Propargyloxy-3-phen0xy-2-carbamyl propane 1 mol of l-propargyloxy-3-phenoxy 2 propanol is treated in the presence of 1 mol of diethyl aniline with 1.5 mol phosgene in toluene solution.

After separation of the hydrochloride amine followed by elimination of the excess phosgene, the chloro-carbonate obtained is treated in gaseous ammonia.

200 ml. of water is added to dissolve the ammonium chloride: The product crystallises immediately. It is dried, washed in water, then recrystallised in absolute alcohol. The final product has a M.P. of 98 C.

EXAMPLE 7 l-Propargyloxy-S-butoxy propane 3-butoxy-1-propanol and 1-allyloxy-3-butoxy propane is first prepared by treating in succession 1,3-propanediol in boiling toluene, in the presence of sodium with butyl bromide and, then with allyl bromide.

The ethylene derivative obtained (E/0.05:-55) is dibrominated by action of bromide in carbon tetrachloride at 8 C. 1 mol of dibrominated compound is purified by distillation and then treated with 3 mols of sodium amide in suspension in liquid ammonia.

After evaporation of the ammonia and extraction in ether, the oxydeacetylene ether is distilled: E/0.4: C.

The compounds listed in Tables I, II and III below have been specially prepared as described above, the tables also give experimental and theoretical data concerning the various compounds in the tables.

In Table I the compounds have the basic formula various groups corresponding to R being given in the first column of the table.

TABLE I Analysts Theoretical Empirical Molecular formula weight ND C H O N Cl C H CH3 C H zO 144, 166 1. 4536 58. 31 8. 40 8. 38 -C1H5 0311 403 158, 192 1, 4502 60. 74 8. 92 8. 84 -CHz-CH=CH C H O; 170, 202 1. 4639 63. 50 8. 29 8. 15 CHz-C CH CnH O 168,186 1. 4738 64. 27 7. 19 7. l2 (CH2)2CH C H O 172, 248 1. 4490 62. 76 9. 36 9. 22 CH(CH3)2 CgHmO; 172, 248 1. 4468 62. 76 9. 36 9. 32 (CH2)aCH Owl-1 0; 186, 244 1. 4494 64. 49 9. 74 9. 51 OHCH(CH:)2 CIOIIHOQ 186,244 1. 4468 64. 49 9. 74 9. 64 CH(CH )C H CmIImO 186, 244 1. 4478 64. 49 9. 74 9. 64 *C(CH:4)3 C1uH1gO3 184, 244 1. 4471 64. 49 9. 74 9. -(CH2)4CH CnHgmOp, 200, 270 1. 4451 65. 96 10. O7 9. C5Hg 0 11 0 198 254 1 4732 66. 67 9. 15 8. 96 CuH 1 0 211 00 212, 280 1. 4759 67. 89 9. 50 9. 33 -(CH2)2C1 C5H O Cl 192, 641 1. 4748 49. 88 6. 8O 6. 63

TABLE I-Continued Analysis Theoretical Actual Empirical Molecular formula weight N 0 H 0 N Cl C H O N C] -(CH2)3C1. C H15O9Cl 206,667 1.4719 52.30 7.32 23.22 17.16 52.49 7.20 23.40 (CH2)4Cl- 01011170801 0,693 1.4725 54.42 7.76 21.75 16.07 54.39 7.76 21.90 (CH2)2'-.N(C4Ha)0 CuHzgNOr 243,296 1.4874 59.24 8.70 26.30 5.76 59.23 8.86 26.49 (CH7)4N(C4H3)O C H NO4 271,348 1 4861 61.96 9.29 23.59 5.16 61.88 9.22 23.72 (CH2)3 N(C4Hfl)0 0 311 190 257,322 1 4868 60.67 9.01 24.87 5 44 60.43 9.16 25.06 11 m 0 11 0 206,232 1 5280 69.88 6.84 23.27 69.76 6.88 24.49 CHz-C H5 0 E160; 220,258 1.5197 70.89 7.32 21.79 70.74 7.19 22.04 CH2CH=CHC6H 01 K 0; 246,294 1.5451 73.14 8.37 19.49 72.94 7.24 19.63 -2-4(iC H1)(CH )C H; 0 811120 262,336 1 5150 7.26 8.45 18.30 73.21 8.30 18.54 CO+CH )C6H4- 01411 60 248,268 1.5413 67.73 6.50 25.78 67.59 6.46 25.90 4-(OOCH GH )C5H4 015111 04 262,294 1 5473 68.68 6.92 24.40 68.52 6.92 24.63 -2-C Hr=: 0 611 50 256,288 1 5935 74.98 6.29 18.73 74.88 6.16 19.06 4ClC5H C HmClOa 240,681 1 540 59.88 5.44 19.94 59.72 5.57 20.11 3(--CF )C5H4 C H F O 274,234 1 4802 56.93 4.78 17.50 56.85 4.65 2(CH9)C6H5 0 11 0 220,258 1 5250 70.89 7.32 21. 79 70.77 7.25 21.94 1-C 9H 4:. C16H 5O 256,288 1.5910 74.98 6.29 18.73 74.81 6.18 18.97 (OH2)2-0-G6H C 4H O 0,284 1.5202 67.18 7.25 25.57 67.01 7.23 25.77 C(OHa)2'+.C6H C H 0 248,31 1.5103 72.55 8.12 19.33 72.45 8.22 19.52 (CHM-09H; (1 11 0 234,284 1.5159 71.77 7.74 20.49 71.76 7.94 20.53

In Table II the compounds have the basic formula H- OCONH2 tives which cause slight transient variations of tension in the cardiovascular system only when administered intravenously in strong doses.

In the case of human beings the derivatives of the in- (Niko-B3 ventlon have been used to effect cures 1n the cases of various groups corresponding to R bemg given 1n the (1) great anxiety of a patlent sufiermg from Parkmsons first column of the table. dlsease.

TABLE II Analysis Elementary Calculated Found Empirical Molecular R3 or A! formula weight N C H O N Cl C H O N 0 (CHM-CH3 CnHnNOq 229,270 1.4642 57.62 8.35 27.91 6.11 8.32 27. 6.23 CH3 CgH13NO4 51.33 7.00 34.19 7.48 7.12 34.22 7.52 CH2CH=CH2 C10H15N04 z- 56.32 7.09 30.01 6.57 7.04 30.22 6.71 --CH2C,ECH C10H15NO4 56.86 6.20 30.30 6.63 6.23 30.41 6.82 (CH2)2-CH6 C10H17NO4f 55.79 7.96 29.73 6.51 7.98 29.84 6.60 -CHzCH-(CHs)2 C11H10NO4 57.62 8.35 .27.91 6.11 8.52 28.16 6.11 -CH(C2H5)CH5 o flmNol 57.62 8.35 27.91 6.11 8.24 27.89 6.18 (CH2)4CH3 C12H21NO4 59.24 8.70 26.31 5.76 8.51 26.44 5.82 --CH(CHa)z C10H17NO4 55.80 7.96 29.73 6.51 8.03 29.95 6.68 -C2H5 O5H15N0. 53.72 7.51 31.81 6.96 7.69 31.75 6.88 c-(cHQ: cuflmNol 1 57.62 8.35 27.92 6.11 8.29 28.04 6.25 -C5H11 C13H21N04; 61.15 8.29 f 25. 07 5.48 8. 24.89 5.29 -05H C12H11N04 59.73 7.94 "26.52 5.81 7.96 26.77 5.86 (oHmcl CIIHHNO4C1 45.87 5.99 27.16 5.94 6.09 27.12 5. 86 C13H15NO41- 62.64 6.07 25.67 5.62 6.24 25.56 5.72 CH2-COH5 C14H17N04E 63.86 6.51 24.31 5.32 6.63 24.24 5.30 2-(CH9)O1H5 OHHuNOr 63.86 6.51 24.31 5.32 6.30 24.50 5.44 awmcum C14H22N205 317,260 53.00 4.45 20.17 4.42 4.30 4.58

(2) anxiety crises in a patient having gross cardiac insufficiency and who had been treated with digitalis for 10 years.

(3) melancholia and insomnia with violent and persistant headaches in a patient suffering from anxiety due to anxiogenic proximity to a psychopath.

(4) progressive decline of intellectual ability due to a minor depressed condition.

In Table III the compounds have the basic formula CHz-O(CH2)2CECH H2--O a the various groups corresponding to R R and R being given in the first three columns of the table.

TABLE III Analysis Elementary Calculated Found Empirical Molecular R; R R formula. weight N 0 H 0 N C H O N H OH H 130,140 1. 4748 55.37 7.75 36. 88 55. 39 7.74 37.04 H H 04H CmHmOi 170,244 1. 4332 70.55 10.66 18.79 70.48 10.61 19.01 H OOONH: CONHZ 0 131919905 216,192 44.44 5.60 37.00 12.96 44.34 5. 72 37.14 12.81

The derivatives of the inventions have been tested on The embodiments of the invention in which an exclusive animals to give myo-relaxing properties by depression of the intercalary neurones of the vertebra marrow. These also act as tranquillers. They have. no hypnotic, curarising or neuroleptic action. The smooth muscular fibre of the autonomous nervous system is unaffected by the deriva- 75 property or privilege is claimed are defined as follows:

1. 1-propargyloxy-2-carbamoyloxy 3 propyloxy propane.

(References on following page) References Cited UNITED STATES PATENTS OTHER REFERENCES Houben-Weyl: Methoden Der Organischen Chemie, 10

Band VI/ 3, Saverstolf Verbindunjen I, Teil 3, pp. 40-44 (1965).

Adams et 211.: Chemical Reviews, volume 65, pp. 567 and 570 (1965).

Wagner et al.: Synthetic Organic Chemistry, pp. 645- 647 and 483-484 (1963).

Stecher, editor: Merck Index of Chemicals and Drugs, seventh edition, p. 667 (1960).

Wagner et al.: Synthetic Organic Chemistry, 1953, pp. 233-234. 7

CHARLES B. PARKER, Primary Examiner C. F. WARREN, Assistant Examiner US. Cl. X.R. 

